Sickle cell disease (SCD) is the commonest genetic disorder in the World. It is most prevalent in Africa. We have established SickleGenAfrica:Sickle Cell Disease Genomics Network of Africa to build capacity locally to enable African scientists study genomics of SCD on the continent. The network consists of a core of investigators in nine institutions in four sub-Saharan African (SSA) countries (Cameroon, Ghana, Nigeria and Tanzania). Our prior studies showed that 1.8% of births in Ghana are affected by SCD. Penicillin prophylaxis in neonates has reduced mortality in SCD, however, this progress has not been matched by advancements in reducing deaths due to other causes. End-stage organ damage is now the leading cause of death among SCD patients in the West and it is poised to become the major cause of death in Africa once prevention and prompt management of infections becomes widely implemented on the continent. Inflammatory molecules such as free heme released from hemolysis cause severe tissue injury that ultimately causes organ damage in SCD. Malaria causes severe intravascular hemolysis and potentially exacerbates hemolysis-related tissue damage in SCD uniquely in Africa. There is a hierarchy of cytoprotective proteins that neutralize the inflammatory molecules released by hemolysis. Studies in transgenic SCD mice indicate some of these cytoprotective proteins such as hemopexin and heme oxygenase-1, influence cardiopulmonary and vascular dysfunctions in SCD. Although these findings have not been validated in patients, we have discovered wide variations in the level of several key hemolysis cytoprotective proteins among patients, suggesting that these proteins modify the clinical phenotype of SCD perhaps most strongly in Africa. Hitherto, the genetics of this variation has not been defined. In addition, the functional murine studies are limited to a few organ systems, and to scientists in the West, since transgenic sickle mice colonies are not available in institutions in Africa. We seek to address these gaps by accomplishing seven objectives: (1) Phenotype 7, 000 SCD patients and controls in four SSA countries; (2) perform three collaborative genetic research project each with a functional validation study in transgenic sickle mice; (3) Establish a molecular hematology and sickle cell mouse core in Ghana; (4) Leverage an existing H3Africa biorepository to establish a SCD biorepository core in Nigeria; (5) Establish a bioinformatics core at the University of Pittsburgh to analyze the genomics data obtained by the H3Africa Center and to provide expertise to upgrade bioinformatics nodes in Ghana in partnership with H3ABionet; (6) Implement a career pipeline model to train future science leaders in Africa in blood disorders research; (7) establish a cross cutting Administrative core enabling synergy and coordination of network activities with a robust sustainability plan for the H3Africa Center. The University of Ghana is submitting this application with strong institutional support from the University of Pittsburgh.